CN102712946A - Sensor layers and methods related thereto - Google Patents

Abstract

Sensors for measuring an analyte in a subject comprising at least one electrode having an electroactive surface, at least one interferent-reducing layer comprising vinyl ester monomeric units disposed distally from the electroactive surface, an enzyme layer disposed distally from the electroactive surface and a flux-limiting membrane disposed over the at least one interferent-reducing layer and the enzyme layer. Methods of measuring an analyte in a subject comprising providing the electrochemical analyte sensor, contacting a sample comprising an analyte and an interferent with the at least one interferent-reducing layer comprising vinyl ester monomeric units, and measuring the analyte, where the amount of interferent reaching the electroactive surface is reduced.

Description

Sensor layer and relative method

Technical field

The disclosure relates generally to stop the kind polymer layer that transports and the equipment that comprises it of impact analysis thing sensor performance.More specifically, the disclosure relates at least one that be used for analyte detection equipment and comprises the vinyl ester monomers unit, can stop that the obscurant of this type kind transportation reduces layer.

Background technology

Between many decades, various analyte-metering facilitys of measuring various analytes have been developed in the past.Some analyte-metering facilitys are continuous device basically, and other analyze a plurality of discontinuous blood samples.Some analyte-metering facilitys be subcutaneous, in skin or blood vessel equipment, it is normally invasive or minimum invasive, and other right and wrong in essence are invasive.The measuring technology that these equipment use comprises enzyme, chemistry, physics, electrochemical, Spectrophotometric, optically-active, calorimetric, radiation measurement and similar techniques, and the output signal of indication analytes of interest analytes concentration generally is provided.The output signal is original signal normally, and the user that it is used for to this equipment of use such as patient or doctor, provides the useful value of analytes of interest analytes.Usually; These analyte-metering facilitys comprise the film system; It starts to control production of hybrid seeds class---such as acetaminosalol, hydroxyurea, potassiumiodide, vazadrine and other compounds---effect of flow, because can cause or help false sensor reading in the title product electrochemical analysis that they exist in blood.But the routine analysis thing-metering facility of use or binding film system suffers multiple shortcoming.

Summary of the invention

Generally speaking, disclose and described unitary at least one obscurant of arranging away from the electroactive surface of electrochemical analyte sensor and sensor module of vinyl ester monomers that comprises and reduce layer.This transmitter provide to the obscurant kind effectively stop and with rapid chemical, electricity and the physical equilibrium of their environment, the result provides quick and accurate analyte level.This transmitter is particularly useful for requiring the application of stricter sensing, in the ICU monitoring.

In first kind of embodiment, electrochemical analyte sensor is provided.Electrochemical analyte sensor comprises at least one electrode with electroactive surface.Comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and arranges away from electroactive surface.The enzyme layer is arranged away from electroactive surface.Analyte flow restriction film is arranged at least one obscurant to be reduced on layer and the enzyme layer.

In the first aspect of first kind of embodiment, at least one obscurant reduce layer than enzyme layer further from electroactive surface.

In the second aspect of first kind of embodiment, the enzyme layer reduces layer further from electroactive surface than at least one obscurant.

In the third aspect of first kind of embodiment, the enzyme layer reduces between the layer at least two obscurants, and at least one obscurant reduces layer and comprises the vinyl ester monomers unit.

In the fourth aspect of first kind of embodiment, electrochemical analyte sensor further comprises the hydrophilic polymer layer that directly contacts with electroactive surface.

First kind of embodiment the 5th aspect, electrochemical analyte sensor further is included in the hydrophilic layer between electroactive surface and the enzyme layer.

First kind of embodiment the 6th aspect, electrochemical analyte sensor further is included in electroactive surface and at least one obscurant and reduces the hydrophilic layer between the layer.

First kind of embodiment the 7th aspect, it is ethylene-vinyl acetate copolymer that at least one obscurant reduces layer.

In the eight aspect of first kind of embodiment, at least one obscurant reduces layer and comprises about 33wt.% or the vinyl acetate content of wt.% still less.

First kind of embodiment the 9th aspect, at least one obscurant reduces layer and comprises about 25wt.% or the vinyl acetate content of wt.% still less.

First kind of embodiment the tenth aspect, at least one obscurant reduces layer and comprises about 18wt.% or the vinyl acetate content of wt.% still less.

First kind of embodiment the tenth on the one hand, at least one obscurant reduces layer and comprises about 12wt.% or the vinyl acetate content of wt.% still less.

In second kind of embodiment, the electrochemical analyte sensor assembly is provided.Electrochemical analyte sensor comprises at least one electrode with electroactive surface.Ethylene-vinyl acetate copolymer arranges that away from electroactive surface ethylene-vinyl acetate copolymer has vinyl acetate content or its mixture that is selected from about 12wt.%, about 18wt.%, about 25wt.%, about 33wt.%.The enzyme layer arranges that away from ethylene-vinyl acetate copolymer wherein the enzyme layer comprises the mixture of P-FAD and poly-N-vinyl pyrrolidone.

In the third embodiment, a kind of method is provided.Said method comprises provides electrochemical analyte sensor, and it has unitary at least one obscurant of the vinyl ester monomers of comprising and reduces layer; And the sample that comprises analyte is contacted with obscurant, reduce the amount of the obscurant that arrives electroactive surface whereby.

In the first aspect of the third embodiment, wherein sample is the body internal jugular vein blood of object.

In the second aspect of the third embodiment, wherein electrochemical analyte sensor is arranged in the conduit.

The accompanying drawing summary

Fig. 1 has shown the amperometric sensor of flex circuits (flex circuit) form according to embodiment of the present invention, and it has the working electrode that limiting membrane covers.

Fig. 2 has the disclosed sectional view that limits the working sensor electrode part of layer like this paper.

Fig. 3 has the disclosed sectional view that limits the working sensor electrode part of layer like this paper.

Fig. 4 has the disclosed sectional view that limits the working sensor electrode part of layer like this paper.

Fig. 5 is the side-view that has according to the multi-cavity catheter of the sensor module of embodiment of the present invention.

Fig. 6 is the details according to the far-end of the multi-cavity catheter of Fig. 5 of embodiment of the present invention.

Detailed Description Of The Invention

Following description and the detailed diagram of embodiment the certain exemplary embodiment of open invention.Those skilled in the art will recognize that existence can comprise of the present invention many variants and modifications within the scope of the present invention.Therefore, the description of some illustrative embodiments does not plan to limit scope of the present invention.

Generally speaking; Comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and arranges away from the electroactive surface of electrochemical analyte sensor; So that effectively stopping/reducing the obscurant kind to be provided; And with rapid chemical, electricity and the physical equilibrium of their environment, the result provides quick and accurate analyte level.On the one hand, comprise that unitary at least one obscurant of vinyl ester monomers reduces layer away from electroactive surface but more arrange near electroactive surface than enzyme layer, and play a part to stop/reduce obscurant.Aspect this, comprise that the unitary layer of vinyl ester monomers allows to pass through to arrive electroactive surface from the hydrogen peroxide of enzyme layer.

On the other hand, comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and arranges away from electroactive surface and further from the enzyme layer.Comprise that the unitary layer of vinyl ester monomers stops/reduce obscurant.At least one obscurant reduces layer can further comprise obscurant scavenging agent (for example, can remove, fetter (bind up) or the biologically active agent of inactivation obscurant) basically, for example, and H ₂O ₂-degrading enzyme is such as but not limited to Selenoperoxidase (GSH px), contains protoheme px, eosinophile peroxidase, thyroid peroxidase or horseradish peroxidase (HRP).Scavenging agent can work in comprising the unitary obscurant minimizing of vinyl ester monomers layer.

On the other hand, comprise the unitary a plurality of layers of vinyl ester monomers away from the electroactive surface layout, the enzyme layer is arranged between a plurality of layers.Arbitrary layer of a plurality of layers stops/reduces obscurant effectively.At least one obscurant reduces layer and can further comprise like above-mentioned scavenging agent.

Definition

In order to promote to understand all respects that this paper is open and describe, below as give a definition.

The term " analyte " that this paper uses refers to analyzable substances of interest or chemical ingredients in biological fluid (for example blood) without limitation.Analyte can be present in the biological fluid naturally, and analyte can be introduced in the body, or analyte can be chemical reactant or chemical product that the enzymatic of meta-bolites or the substances of interest of substances of interest produces.Preferably, analyte comprises the chemical entities that can also quantitatively produce amperometry or the detectable electrochemical reaction product of volt-ampere analysis (voltammetrically) with at least a enzyme reaction.

The phrase that uses like this paper and term " analysis measurement equipment ", " transmitter " and " sensor module " refer to detect the field (area) of the analyte-monitoring equipment of at least a analyte without limitation.For example; Transmitter can comprise non-conduction portion, at least one working electrode, reference electrode and counter electrode (optional); Form the electrochemical reaction surface in a position of non-conduction portion and form electrical connection and the one or more layers of formation on the electrochemical reaction surface in another position of non-conduction portion.

The phrase that uses like this paper " can ", when the structure function associated narration that refers to narration, comprise that wherein institute's narrative structure can the actual all conditions of carrying out institute's narrate function.For example, phrase " can " be included in normal operating condition, experiment condition or laboratory condition and can not occur during the normal running or maybe absent variable condition under carry out function.

The term " cellulose acetate butyrate (cellulose acetate butyrate) " that uses like this paper refers to through making Mierocrystalline cellulose and diacetyl oxide contact the compound that obtains with butyryl oxide without limitation.

The term that uses like this paper " comprises " with its grammer and is equal to speech and " comprising ", " containing " or " being characterised in that " synonym, and is that comprise formula or open, do not get rid of key element or the method steps do not narrated in addition.

The analyte concentration monitoring that the phrase " successive analysis thing sensing " that uses like this paper and " lasting analyte sensing " (being equal to speech " continuously " and " constantly " with phraseological) refer to continuously without limitation, constantly and/or discontinuously (but regularly) carries out for some time.

The phrase " glucose sensing continuously " that uses like this paper refers to continuously without limitation, constantly and/or discontinuously (but regularly) carry out the glucose concn monitoring of for some time.For example, the time period can be a scope from part second to for example 1,2 or 5 minute or the longer timed interval.

The term " crosslinked (crosslink) " that uses like this paper refers to be connected (for example, polymkeric substance and/or proteinic adjacent chain) through forming covalent linkage or ionic linkage with " crosslinked (crosslinking) " without limitation.Can be crosslinked through known technology realization, for example, thermal response, chemical reaction or ionizing rays (for example, electron beam irradiation, UV radiation, X-ray or gamma radiation).For example, dialdehyde will produce the chemically crosslinked of enzyme and/or hydrophilic polymer such as the reaction of LUTARALDEHYDE and hydrophilic polymer-enzyme composition.Crosslinked can with the sterilization of equipment, for example, carry out (commensurate) simultaneously through the sterilization of electron beam irradiation or gamma radiation.

Phrase " hydrophilic polymer-enzyme composition " refers to physics or chemical mixture, the physical blending thing of at least a enzyme and at least a hydrophilic polymer, evenly or heterogeneous mixture, continuously or discontinuous phase, micella or dispersion-s without limitation.Hydrophilic polymer-enzyme composition can further comprise at least a protein, or natural or synthetic materials.

The term " break-in (break-in) " that uses like this paper refers to the time remaining of transmitter after disposing without limitation, wherein the output of the electricity of transmitter transmitter with reach constant value after solution contacts.Break-in comprises through applying different voltages with different the sensors configured electron device is set, with high voltage be provided with start and then reduce the voltage setting and/or with negative current with constant current density pretreatment operation electrode.Break-in comprises the chemistry/electricity balance of one or more sensor elements such as film, layer, enzyme and electron device, and can before calibrating sensors output, carry out.For example, after the electromotive force input pickup, break-in immediately will be from the substantially invariable electric current output of transmitter.As an example, after solution contacts, for electrochemical glucose sensor break-in immediately will be illustrated in dispose after about 30 minutes or shorter within+/-the electric current output of the calibration glucose concn of 5mg/dL.Term " break-in " is recorded in the document and by electrochemical glucose sensor field technician well to be understood, but for glucose sensor its can be illustrated as reference glucose data (for example from SMBG meter)+/-time within the measurement of glucose sensing data of 5mg/dL.

The electrode surface that refers to take place electrochemical reaction like the phrase " electroactive surface " of this paper use without limitation.For example, under predetermined electromotive force, H ₂O ₂Electroactive surface reaction with working electrode produces 2 proton (2H ⁺), 2 electronics (2e ^-) and 1 oxygen molecule (O ₂), the detectable electric current of electron production wherein.Electroactive surface can comprise chemistry or covalently bound tackifier on the part at least at it, such as aminoalkyl group silane and analogue.

As used herein term " object " refers to Mammals, especially people and domestic animal without limitation.

Term " obscurant (interferant) ", " obscurant (interferent) " and " disturbance type " that uses like this paper refers to without limitation otherwise can disturb the measurement of analytes of interest analytes in transmitter can not accurately represent the Substrate (effect) and/or the kind of the signal of analysis measurement value with generation.For example, in electrochemical sensor, disturbance type possibly be oxidation potential basically with the oxidation potential eclipsed compound of measured analyte.

The phrase " enzyme layer " that uses like this paper refers to permeable or semipermeable partition without limitation, and it comprises the one or more permeable reactants that when measuring analytes of interest analytes, adopt and/or the zone of co-reactant.As an example, the enzyme layer comprises the fixed P-FAD, and the electrochemical reaction of this enzyme catalysis glucose and oxygen is to allow measure glucose concentration.

The term " limiting membrane " that uses like this paper refers to semipermeable partition, its restriction or inhibition oxygen and the flow of other analytes through semipermeable partition.Preferably, the oxygen of enzyme layer and the flow of other analytes below film restriction or inhibition arrive.For example, for glucose sensor, film is preferably with the excessive oxygen that provides of non-rate limiting.As a result, compare than the upper limit that obtains without this film, the linear upper limit of this glucose measurement expands much higher value to.Phrase " limiting membrane " and " analyte flow restriction film " are in the interchangeable use of this paper.

The phrase " vinyl ester monomers unit " that uses like this paper refers to that compound and material that the polymerization by the unsaturated monomer with ester functional group forms form.For example, gathering (ethylene-vinyl acetate) and its multipolymer is to comprise the unitary compound of vinyl ester monomers.

Sensing system and sensor module

The aspect of disclosure invention relates to the application of analyte sensor system, the concentration of the concentration of the concentration of said analyte sensor systematic survey analytes of interest analytes or indication analyte or the material of existence.This sensing system is a continuous device, for example can be used as subcutaneous, in skin (for example, wear skin) or blood vessel equipment, or its part.Analyte sensor can use combination enzyme, chemistry, electrochemical method or these methods, carries out analyte-sensing.Output signal original signal normally, it is used for to the user that possibly use this equipment---such as patient or doctor---provides the useful value of analytes of interest analytes.Therefore, suitable smoothing (smoothing), calibration and appraisal procedure can be applied to original signal.

Usually, transmitter comprises the electroactive surface that the part at least of the working electrode that is centered on by a plurality of layers exposes.Preferably, being deposited upon on the electroactive surface of part at least of transmitter (working electrode and randomly reference electrode) is protected from coenocorrelation influence and/or restriction or stops obscurant so that electrode surface exposed is provided.Enzyme is deposited upon on the electroactive surface of part at least of at least one working electrode.

The medical supply that an illustrative embodiments utilization of describing in detail below has the glucose sensor assembly is such as conduit.On the one hand, the medical supply with analyte sensor assembly is provided, has been used to insert the vascular system of object.Medical supply with analyte sensor assembly can comprise the electronic unit that links to each other with transmitter that is associated with it and be used to receive and/or the receptor of process sensor data.Although the several exemplary embodiment of continuous glucose sensor is diagram and description in this article; But be to be understood that disclosed embodiment can be fit to any equipment, the concentration that said equipment can continuous basically or basic test constantly analytes of interest analytes also is used to provide fast and the output signal of representing this analyte concentration accurately.

Electrode and electroactive surface

The electrode and/or the electroactive surface of disclosed transmitter of this paper or sensor module comprise conductive of material, such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conducting polymer, alloy, printing ink etc.Although electrode can form (bulk metal is processed (bulk metal processing), metal refining is first-class in substrate) through multiple manufacturing technology, the electrode that forms electrode or formation electric wire from the screen printing technique that uses conductivity and/or catalytic ink can have superiority.Conductive ink can use precious metal such as platinum and/or palladium catalysis.

On the one hand, the electrode of transmitter or sensor module and/or electroactive surface form on such as flex circuits in flexible substrates.On the one hand, flex circuits is the part of transmitter and comprises substrate, conduction track (conductive trace) and electrode.Track and electrode can for example use silk screen printing or ink deposition technology to shelter and be imaged onto in the substrate.The electroactive surface of track and electrode and electrode can be made up of such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conducting polymer, alloy, printing ink etc. conductive material.

On the one hand, provide counter electrode to be equilibrated at the electric current that the working electrode place is produced by measured kind.Under the situation based on the glucose sensor of P-FAD, measured kind is H at the working electrode place ₂O ₂According to following reaction, the P-FAD Catalytic Oxygen becomes hydrogen peroxide and gluconate: glucose+O with conversion of glucose ₂→ gluconate+H ₂O ₂The H that working electrode carries out ₂O ₂Any oxygen of being existed of oxidation or in the reduction balance of other reducible kinds at counter electrode place.H by glucose oxidase enzyme reaction generation ₂O ₂In working electrode surface place reaction and produce 2 proton (2H ⁺), 2 electronics (2e ^-) and 1 oxygen molecule (O ₂).

On the one hand; Other electrode can be included in transmitter or the sensor module; For example; Three-electrode system (working electrode, reference electrode and counter electrode), and/or be configured to baseline deduction electrode (baseline subtracting electrode) or dispose the one or more working electrodes that are used to measure other analyte.Two working electrodes can be each other very near placement, and very near reference electrode.For example; Multi-electrode system can be configured; Wherein first working electrode is configured to measure first signal that comprises glucose and baseline, and other working electrode similar basically with first working electrode, that do not have enzyme to be placed on it is configured to measure the background signal of only being made up of baseline.Like this, the background signal that is produced by other electrode can be deducted the signal that has only glucose that does not have baseline fluctuation and/or electrochemical activity disturbance type basically to produce from the signal of first working electrode.

On the one hand, transmitter comprises 2 to 4 electrodes.Electrode can comprise, for example, and counter electrode (CE), working electrode (WE1), reference electrode (RE) and optional second working electrode (WE2).On the one hand, transmitter has CE and WE1 at least.On the one hand, use to add WE2, it can further improve the tolerance range of sensor measurement.On the one hand, can use to add second counter electrode (CE2), it can further improve the tolerance range of sensor measurement.

Before applying any layer subsequently, can handle electroactive surface.Surface treatment for example can comprise chemistry, plasma body or laser treatment part electroactive surface at least.For example, electrode can contact with one or more tackifier chemistry or covalency.Tackifier can comprise for example aminoalkyl group organoalkoxysilane, epoxy alkyl organoalkoxysilane and analogue.For example, one or more electrodes can contact with the solution chemistry or the covalency that comprise 3-glycidoxypropyl trimethoxy alkyl silane (3-glycidoxypropyltrimethoxysilane).

In some optional embodiments, can increase the exposed surface area of work (and/or other) electrode through the xsect that changes electrode itself.The surface-area that increases working electrode can be favourable providing aspect the increase signal of analyte concentration response, and it can help to improve for example SNR again.The xsect of working electrode can be defined as any rule or irregular, circular or non-circular structure.

In some applications, cell is attacked or transmitter is arrived in cell migration, especially after first day that implants, can cause the reduction of equipment susceptibility and/or function.But, when the electroactive surface of inoperative electrodes exposed applies with described herein layer, realize reducing or eliminating the deposition of local cells contact and/or electroactive surface.The additive method that prevents the electroactive surface of cells contacting inoperative electrodes exposed can combine this paper disclosed method to use with structure.Therefore, in some optional embodiments, the electroactive surface of one or more inoperative electrodes (for example, reference electrode (RE), counter electrode (CE) or supporting electrode) can apply can eliminate or reduce stained layer (" stain-proofing layer ").For example; The electroactive surface of inoperative electrode can apply to be selected from following material: the tetrafluoroethylene of cellulose ester verivate, siloxanes, tetrafluoroethylene, ethylene-tetrafluoroethylene copolymer, polyolefine, polyester, polycarbonate, Biostatic, urethane homopolymer, polyurethane copolymer, urethane terpolymer, Vestolen PP 7052 (PP), SE (PVC), gather inclined to one side 1; 1-difluoroethylene (PVDF), polybutylene terephthalate (polybutylene terephthalates) (PBT), polymethylmethacrylate (PMMA), polyetheretherketone (PEEK), urethane, cellulosic polymer, polysulfones, tetrafluoroethylene-perfluor-3; 6-two -4-methyl-7-octene sulfonic acid copolymer (Nafion) and its segmented copolymer comprise; For example, Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock, triblock copolymer, alternating copolymer, random copolymers and graft copolymer.Can use the combination of above-mentioned polymkeric substance.One preferred aspect, stain-proofing layer is the obscurant layer, so that stain-proofing layer reduces or eliminates the diffusion of disturbance type with respect to for example hydrogen peroxide effectively.

On the one hand, stain-proofing layer is made up of one or more cellulose derivatives.Cellulose derivative can include, but not limited to cellulose ester and ether of cellulose.Generally speaking; Cellulose derivative comprises polymkeric substance such as rhodia, cellulose acetate butyrate, 2-Natvosol, CAP, cellulose acetate propionate, acetic acid trimellitic acid Mierocrystalline cellulose etc., and they and other cellulose family monomers or monomeric multipolymer of non-cellulose class and terpolymer.Though general preferred cellulose analog derivative also can use to have with other of cellulose derivative similarity and gather polysaccharide.

On the one hand, the stain-proofing layer that is deposited on the electroactive surface of at least one inoperative electrode is formed by cellulose acetate butyrate.Cellulose acetate butyrate is to have the two cellulosic polymer of ethanoyl and butyl group, and also can comprise hydroxyl.Can use have about 35% or still less ethanoyl, about 10% to about 25% butyryl radicals with supply the cellulose acetate butyrate of the hydroxyl of residuum.Also can use to have about 25%, still, can use the ethanoyl and the butyryl radicals of other amounts to about 34% ethanoyl and about 15% cellulose acetate butyrate to about 20% butyryl radicals.Preferred cellulose acetate butyrate comprises about 28% to about 30% ethanoyl and about 16% to about 18% butyryl radicals.

On the one hand, stain-proofing layer can be the vinyl polymer that is suitable for sensor device.The examples of material that can be used for making stain-proofing layer comprises having the unitary vinyl polymer of Vinyl Acetate Monomer.In preferred embodiment, stain-proofing layer comprises having the plastic of poly vinyl acetate (EVA polymkeric substance) of vinyl acetate content less than 33wt.%.Other aspects, stain-proofing layer comprise the plastic of poly vinyl acetate (EVA polymkeric substance) with the about 25wt.% of vinyl acetate content.Preferred aspect, stain-proofing layer comprises the plastic of poly vinyl acetate (EVA polymkeric substance) with the about 18wt.% of vinyl acetate content.

Therefore, all respects of and the transmitter described open at this paper, transmitter further comprises reference electrode, counter electrode, supporting electrode or its combination, arranges at least one stain-proofing layer above that.

At least one obscurant reduces layer

Obscurant can be molecule or other kinds, and it can directly or through electron transfer agents be reduced or oxidation in the electrochemically reactive surface of transmitter, produces false positive analyte signal (for example, the relevant signal of non-analyte).It is higher than real analyte concentration that this false positive signal generally causes the analyte concentration of object to show.For example, under the situation of hypoglycemia, when object had absorbed obscurant (for example, acetaminosalol), false high glucose signals can cause object or healthcare provider to believe that their blood sugar is normal, or in some cases, is hyperglycemia.As a result, object or healthcare provider possibly make inappropriate or incorrect processing decision.In other incidents, a large amount of electrochemistry kinds that in the enzyme layer, produce can or be transported and lose away from electrochemical surface owing to diffusion.

On the one hand, comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and is provided at and reduces basically or limit on the transmitter or sensor module of one or more disturbance types through the there.The disturbance type of glucose sensor comprises; For example, acetaminosalol, xitix, UCB, SUV, creatinine, Dopamine HCL, racephedrine, Ibuprofen BP/EP, levodopa, methyldopa, salicylate, tsiklomitsin, tolazamide, tolbutamide, tri-glyceride, urea and uric acid.Than to the target analysis species, such as hydrogen peroxide, obscurant reduces layer can be more impermeable to one or more disturbance types.On the other hand, comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and is provided at minimizing basically or limits hydrogen peroxide for example on the transmitter or sensor module of diffusion of enzyme layer or transportation.Therefore, when comprising that unitary at least one obscurant of vinyl ester monomers reduces on layer enzyme layer that covers electroactive surface, the hydrogen peroxide of generation will more possibly be detected.

On the one hand; Comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and is and the combination that is selected from following one or more materials: the multipolymer of the tetrafluoroethylene of cellulose ester verivate, siloxanes, tetrafluoroethylene, ethylene-tetrafluoroethylene copolymer, polyolefine, polyester, polycarbonate, Biostatic, the homopolymer of urethane, urethane, the terpolymer of urethane or blend, Vestolen PP 7052 (PP), SE (PVC), gather inclined to one side 1; 1-difluoroethylene (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyetheretherketone (PEEK), urethane, cellulosic polymer, polysulfones, tetrafluoroethylene-perfluor-3; 6-two

-4-methyl-7-octene sulfonic acid copolymer (Nafion) and its segmented copolymer; For example comprise Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock, triblock copolymer, alternating copolymer, random copolymers and graft copolymer.Can use the blend of above-mentioned polymkeric substance.

In one embodiment, comprise that it is the combination of one or more cellulose derivatives that unitary at least one obscurant of vinyl ester monomers reduces layer.On the one hand; Can use blended cellulose ester analog derivative; For example; Cellulose acetate butyrate, CAP, cellulose acetate propionate, acetic acid trimellitic acid Mierocrystalline cellulose and they and other cellulose families or monomeric multipolymer of non-cellulose class and terpolymer comprise top crosslinked modification.Other polymkeric substance, such as the polysaccharide that gathers that has with the cellulose derivative similarity, can be used as interfering material or with top cellulose derivative combination.Cellulosic other esters can be derivative blended with the blended cellulose esters.

On the one hand, use the combination that comprises unitary polymkeric substance of vinyl ester monomers and cellulose acetate butyrate.Cellulose acetate butyrate be have ethanoyl and butyl the two, and the cellulosic polymer of hydroxyl.Can use and have about 35% or ethanoyl still less, about 10% to about 25% butyryl radicals with supply the cellulose acetate butyrate of the hydroxyl of residuum.Also can use to have about 25%, still, can use the ethanoyl and the butyryl radicals of other amounts to about 34% ethanoyl and about 15% cellulose acetate butyrate to about 20% butyryl radicals.Preferred cellulose acetate butyrate comprises about 28% to about 30% ethanoyl and about 16% to about 18% butyryl radicals.

Molecular weight is that about 10,000 dalton are preferred to about 75,000 daltonian cellulose acetate butyrates, preferably from about 15; 000,20,000 or 25,000 dalton are to about 50,000,55; 000,60,000,65,000 or 70; 000 dalton and more preferably use about 65,000 dalton.But, in some embodiments, can use higher or lower molecular weight, perhaps can use the blend of two or more cellulose acetate butyrates with different molecular weight.

Can construct multilayer and comprise unitary polymkeric substance of vinyl ester monomers and cellulose acetate butyrate, reduce layer, in some embodiments, for example, can use two-layer or multilayer to form at least one obscurant.Can expect to use the mixture that in single solution, has the cellulose acetate butyrate of different molecular weight; Or from (for example comprising different molecular weight, different concns and/or different chemical character; The different solutions deposit multilayer cellulose acetate butyrate of cellulose acetate butyrate wt.% functional group) will comprise that maybe the unitary polymkeric substance of vinyl ester monomers is clipped between the derivatived cellulose.Can use other material in casting liquid (casting solution) or dispersion-s; For example, casting auxiliary agent (casting aid), skimmer, surface tension modifier, functionalized agent, linking agent, other polymeric materials, can modification gained layer the material or the like of hydrophilic/hydrophobic.

Comprise that but unitary at least one obscurant of vinyl ester monomers reduces layer direct injection, casting, applies or be impregnated on the electroactive surface (one or more) of transmitter.Can use any known thin film technique to implement the dispersion of interfering material.Two-layer, three layers or multilayer interfering material can apply and solidify and/or dry casting liquid forms through order.

Solid concentration is adjustable in a layer deposition q.s in the casting liquid solid or film on electrode (for example; At single-steeping or in spraying); With form enough stop have oxidation or reduction potential energy otherwise with measured kind (for example, H through sensor measurement ₂O ₂) layer of eclipsed obscurant.For example, the percent solids of casting liquid just only need to be adjustable to individual layer with the deposition q.s, to form the functional interfere with layer prevent basically or to reduce the glucose signals of equal value of the obscurant through sensor measurement.The interfering material of q.s will be to prevent basically or reduce less than about 30,20 or the amount of the glucose signals of equal value of the obscurant of 10mg/dl.For example, at least one obscurant reduces the glucose signals response of equal value that layer preferably is configured to stop basically about 30mg/dl, otherwise this response will be produced through the transmitter that does not have interfere with layer by acetaminosalol.The glucose signals response of equal value that this acetaminosalol produces will comprise the acetaminosalol of therapeutic dose.The layer that any amount of coating that forms with any order or layer can be fit to form the disclosed embodiment of this paper.

On the one hand, comprise that unitary at least one obscurant of vinyl ester monomers reduces on the electroactive surface that layer directly deposits to transmitter or deposits on the material or layer (for example, electrode layer, enzyme layer) that directly contacts with electrode surface.

On the other hand, comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and directly deposits on the electroactive surface of sensor electrode or on material that is in direct contact with it or the layer (for example, electrode layer, enzyme layer).

Still on the other hand, comprise that unitary at least two obscurants of vinyl ester monomers reduce layer material arranged or layer (for example, electrode layer, enzyme layer) between them.

Can use and comprise that unitary at least one obscurant of vinyl ester monomers reduces layer to provide from about 0.05 micron or still less to about 20 microns or more; More preferably from about 0.05,0.1,0.15,0.2,0.25,0.3,0.35,0.4,0.45,0.5,1,1.5,2,2.5,3 or 3.5 micron to about 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 19.5 microns and more preferably still from about 1,1.5 or 2 micron to about 2.5 or 3 microns thickness.In some embodiments, also can expect thicker film, but thinner film generally can be preferred, because they generally have lower influence to hydrogen peroxide from the speed that enzyme membrane diffuses to electrode.

The enzyme layer

Disclosed transmitter of this paper or sensor module comprise with interested analyte and/or are total to the interactional enzyme layer of analyte.On the one hand, the enzyme layer comprises at least one isolating layer that comprises the layer of enzyme or comprise hydrophilic polymer and enzyme mixture.Hydrophilic polymer plays electrode layer, no matter it be separately deposition or with the layer combined deposition that comprises enzyme.On the one hand, the enzyme layer comprises enzyme layer or the hydrophilic polymer-enzyme composition that directly is deposited on the part electroactive surface at least.On the other hand, the enzyme layer comprises that at least one obscurant that directly is deposited at least partly reduces enzyme layer or hydrophilic polymer-enzyme composition on the layer.

On the one hand; The enzyme layer comprises enzyme and is selected from following hydrophilic polymer: poly-N-vinyl pyrrolidone (PVP), poly-N-vinyl-3-ethyl-2-pyrrolidone, poly-N-vinyl-4; 5-dimethyl--2-Pyrrolidone, SEPIGEL 305, gather-N N-DMAA, Z 150PH, polymkeric substance and its multipolymer with ionizable side-chain radical.On the one hand, the enzyme layer comprises P-FAD, poly-N-vinyl pyrrolidone and is enough to the linking agent of the amount of immobilized enzyme.

The molecular weight of enzyme layer hydrophilic polymer is such: when the transmitter initial placement, stop or suppress basically fugitive kind leave sensor environment with more specifically, prevention or suppress the environment that fugitive kind is left enzyme basically.

Hydrophilic polymer-the enzyme composition of enzyme layer can further comprise at least a protein and/or natural or synthetic materials.For example, the hydrophilic polymer-enzyme composition of enzyme layer can further comprise, for example serum albumin, polyallylamine, polyamine and analogue, with and combination.

On the one hand, enzyme is fixed in the transmitter.Enzyme can be encapsulated in the hydrophilic polymer and can be crosslinked or otherwise fix therein.Enzyme can be randomly together with at least a protein and/or natural or synthetic materials is crosslinked or otherwise fixing.On the one hand, hydrophilic polymer-enzyme composition comprises P-FAD, bovine serum albumin and poly-N-vinyl pyrrolidone.Compsn can further comprise linking agent, and for example, dialdehyde is such as LUTARALDEHYDE, with the crosslinked or component of fixing composition otherwise.

On the one hand, other protein or natural or synthetic materials can be got rid of from hydrophilic polymer-enzyme composition of enzyme layer basically.For example, hydrophilic polymer-enzyme composition can be substantially free of bovine serum albumin.The compsn that does not contain BAS requires and can expect for satisfying various governabilities.Therefore, on the one hand, the enzyme layer comprises the linking agent of P-FAD and q.s, and for example, dialdehyde is such as LUTARALDEHYDE, with crosslinked or immobilized enzyme otherwise.Other aspects, the enzyme layer comprises the linking agent of P-FAD, poly-N-vinyl pyrrolidone and q.s, with crosslinked or immobilized enzyme otherwise.

The enzyme layer thickness can be from about 0.05 micron or still less to about 20 microns or bigger, more preferably from about 0.05,0.1,0.15,0.2,0.25,0.3,0.35,0.4,0.45,0.5,1,1.5,2,2.5,3 or 3.5 micron to about 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 19.5 microns.Preferably, the enzyme layer deposits through injection or dip coated, still, also can use the additive method that forms the enzyme layer.Can form the enzyme layer through being coated with one or more layers with predetermined coating solution concentration, insertion speed, the residence time, the thickness dip coated of withdrawing from speed and/or expectation and/or injection.

Analyte flow restriction film

The speed that flows through that on the one hand, analyte flow restriction film (or limiting membrane) is arranged on the above-described subsequent layer, and wherein analyte flow restriction film is changed or changed one or more analytes of interest analytes or common analyte---for example glucose and oxygen---.Although following description relates to the limiting membrane that is used for the electrochemical glucose transmitter,, this limiting membrane also can be modified, and is used for other analytes and common analyte.

On the one hand, limiting membrane comprises semipermeable materials, and its control oxygen and glucose is the flow of surface layer extremely down, preferably with the excessive oxygen that provides of non-speed limit.As a result, the upper limit of the linearity of glucose measurement expands the much higher value of the upper limit that obtains than without limiting membrane to.In one embodiment, limiting membrane shows about 50:1 or is smaller to about 400:1 or bigger that preferably approximately the infiltration of the oxygen of 200:1 and glucose is compared.Can use or combine other limiting membranes, such as having the two film of the hydrophilic and hydrophobic zone of convergency, with control analysis thing and the diffusion of optional common analyte to analyte sensor.For example, suitable membrane can comprise hydrophobic polymer matrix ratio of component such as urethane or polyether urethane urea (polyetherurethaneurea).Limiting membrane can play the effect of obscurant layer to a certain extent, such as hydrophobicity siloxanes urethane such as the combination of Carbosil and hydrophilic polymer such as Vinylpyrrolidone polymer.On the one hand; The material on cambial hydrophobic base basis can be any well known in the art, be adapted at being used as film in the sensor device and have enough perviousness passing it those to allow related compound; For example, to allow oxygen molecule from the sample of inspection, to pass layer so that arrive organized enzyme or electrochemical electrode.For example, also can use non-urethane type layer such as vinyl polymer, polyethers, polyester, polymeric amide or film, track etching polycarbonate, inorganic polymer is such as ZGK 5 and gather carbon siloxanes (polycarbosiloxane), natural polymer such as cellulose family and protein-based material and its mixture or combination.

On the one hand, analyte flow restriction film comprises the polyethylene oxide component.For example, the hydrophobic-hydrophile copolymers that comprises polyethylene oxide is the polyether polyols with reduced unsaturation that comprises about 20% hydrophilic polyethylene oxide.The polyethylene oxide of multipolymer is separated with the hydrophobic polymer component with the hydrophobic part (for example, urethane ester moiety) with multipolymer by the thermodynamics driving partly.The soft section some effects water based on 20% polyethylene oxide that is used to form final blend of multipolymer absorbs (pick up) and with the glucose perviousness of caudacoria.

On the one hand, film comprises semipermeable materials, and the flow of its control oxygen and glucose to below enzyme layer is preferably with the excessive oxygen that provides of non-speed limit.As a result, the upper limit of the linearity of glucose measurement expands the much higher value of the upper limit that obtains than without limiting membrane to.In one embodiment, film shows about 50:1 or is smaller to about 400:1 or bigger that preferably approximately the infiltration of the oxygen of 200:1 and glucose is compared.

The film forming material of structure can be to be suitable for use in to have enough perviousness in the sensor device and pass its vinyl polymer to allow related compound, for example, allows oxygen molecule to pass to arrive organized enzyme or electrochemical electrode.The examples of material that can be used for making film comprises having the unitary vinyl polymer of vinyl ester monomers.In a preferred embodiment, limiting membrane comprises polyethylene vinyl acetate ester (EVA polymkeric substance).In other respects, limiting membrane comprises the methyl methacrylate-butyl methacrylate multipolymer with the EVA polymer blending.EVA polymkeric substance or its mixture can be crosslinked, and be for example, crosslinked with diglycidylether.The EVA film is very resilient, and it can provide elasticity so that through zigzag path to transmitter, for example, gets into the venous anatomy structure.On the one hand, limiting membrane all is the EVA polymkeric substance with comprising that unitary at least one obscurant of vinyl ester monomers reduces layer, but the vinyl acetate content of different %.

Can EVA be provided polymkeric substance from the source of composition with about 40wt.% vinyl acetate (EVA-40).The EVA polymkeric substance preferably is dissolved in the solvent, so that on transmitter or sensor module, spread.Should be according to the ability selective solvent of dissolving EVA polymkeric substance, bonding with promotion and sensor base and enzyme electrodes, and form the solution that can effectively apply (for example, injection is coated with or dip coated).Solvent such as pimelinketone, p-Xylol and THF can be fit to this purpose.Solution can comprise the EVA polymkeric substance of about 0.5wt.% to about 6.0wt.%.In addition, solvent should have enough volatility and evaporate to prevent the problem relevant with the below enzyme so that need not excessively stir, and the volatility of still can not having very much consequently produces the problem relevant with course of injection.In a preferred embodiment, the vinyl acetate component of limiting membrane comprises about 20% vinyl acetate.In preferred embodiment; Limiting membrane is deposited on the enzyme layer to produce from about 0.05 micron or be smaller to about 20 microns or bigger, more preferably from about 0.05,0.1,0.15,0.2,0.25,0.3,0.35,0.4,0.45,0.5,1,1.5,2,2.5,3 or 3.5 micron to about 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 19.5 microns and still more preferably from about 5,5.5 or 6 microns to about 6.5,7,7.5 or 8 microns layer thickness.Limiting membrane can be deposited on the enzyme layer through spraying coating or dip coated.On the one hand, limiting membrane is deposited on the enzyme layer to the solution of the solvent of 99wt.% with about 95wt.% to the EVA polymkeric substance of about 10wt.% through the about 1wt.% of dip coated.

In one side of the present disclosure, electrochemical analyte sensor is provided, it EVA obscurant that comprises the EVA limiting membrane of the qualification compsn that covers the enzyme layer and be different from the flow restriction layer composition reduces layer and part electroactive surface at least.

Biologically active agent

In some optional embodiments, biologically active agent can randomly be incorporated the sensor system into, so that biologically active agent diffuses out the biological environment that gets into proximity sense.In addition or alternatively, can be at outlet position or implant site topical application biologically active agent.Suitable biologically active agent comprises change object those biologically active agents to the tissue response of any transmitter or its parts.For example, biologically active agent can be selected from anti-inflammatory agent, anti-infection agent, narcotic, inflammatory agent (inflammatory agent), growth factor, immunosuppressor, anti-platelet agents, anti-coagulant, anti-proliferative agent (anti-proliferate), ACE inhibitor, cytotoxic agent, anti-barrier cell compound (anti-barrier cell compound), induction of vascular generation compound, antisense molecule (anti-sense molecule) or its mixture.On the one hand, heparin or heparin derivatives are applied to the outmost surface of transmitter.

Be fit to the flexible substrates sensor module that vein inserts

On the one hand, the electrochemical analyte sensor assembly can be arranged to the vascular system that intravenously inserts object.In order in the restricted clearance of the equipment that is fit to the intravenously insertion, to hold transmitter, sensor module can comprise flexible substrates, such as flex circuits.For example, the flexible substrates of configurable flex circuits is thin conducting electrode, and it is coated on non-conductive material such as on thermoplastics or the thermosetting resin.Can on non-conductive material, form the conduction track and be electrically connected with thin conducting electrode.The electrode of flex circuits can be aforesaid.

Flex circuits can comprise at least one reference electrode and at least one working electrode, and this at least one working electrode has electroactive surface, and it can provide detectable electricity output after can detecting the kind interaction with electrochemistry.Flex circuits can also comprise at least one counter electrode.On the one hand, flex circuits comprises two or more working electrodes and two or more counter electrodes.On the one hand, flex circuits comprises two or more working electrodes, two or more blank electrode (blank electrode) and two or more counter electrode.

On the one hand, place the part electroactive surface that comprises unitary at least one the direct contact of obscurant minimizing layer of vinyl ester monomers and at least partly cover the working electrode of flex circuits.Comprise hydrophilic polymer-enzyme composition, can interact so that provide the enzyme layer of the detectable kind of electrochemistry to place like this with the analyte enzymatic, so as at least its part directly contact and at least part cover and comprise that unitary at least one obscurant of vinyl ester monomers reduces layer.Can place limiting membrane, such as the film that changes the analytes of interest analytes flow, so that it covers the hydrophilic polymeric layer, comprises that unitary at least one obscurant of vinyl ester monomers reduces the electroactive surface of part at least of layer and flex circuits.

On the other hand, place and to comprise hydrophilic polymer-enzyme composition, can interact, so that the enzyme layer of the detectable kind of electrochemistry is provided, so that its part directly contacts the electroactive surface of flex circuits working electrode at least with the analyte enzymatic.Comprise that unitary at least one obscurant of vinyl ester monomers reduces layer and is placed direct contact and part cover part enzyme layer at least.Can place limiting membrane, such as the film that changes the analytes of interest analytes flow, so that it covers the hydrophilic polymeric layer, comprises that unitary at least one obscurant of vinyl ester monomers reduces the electroactive surface of part at least of layer and flex circuits.

It is control unit that flex circuits preferably is configured to electricity configurable.The example of flex circuits electrode and its structure are seen the U. S. application number 2007/0202672 and 2007/0200254 of co-assigned, incorporate this paper through reference into their integral body.

Medical supply like above-mentioned suitable sensor module comprises; But be not limited to, central vein conduit (CVC), PAC (PAC), the conduit (PICC) that is used to insert the probe that passes CVC or PAC or pass peripheral IV conduit, peripheral insertion, swan-Ganz catheter, intubator or vein arterial blood management protection (Venous Arterial blood Management Protection) be annex of system (VAMP).The central vein conduit (CVC) or the intravenously equipment that can use or change any size/type are used for using with sensor module.

For aforementioned discussion, the enforcement of transmitter or sensor module is disclosed as and is placed in the conduit, still, considers above-mentioned other equipment and incorporates it into aspect of the present invention.Sensor module will preferably be applied to conduit to flush with the OD of duct conduits.This can be for example OD through the thermal distortion pipeline so that realize for transmitter provides dimple (recess).Sensor module can combine in position; And (promptly with tackiness agent; Urethanum, 2-part epoxy (2-partepoxy), vinylformic acid etc.) sealing, this tackiness agent holds out against bending/peel off, and adheres to the material of urethanum CVC pipeline and transmitter.Small diameter wire can be connected with sensor module through welding, pressure bonding or conduction epoxy.These lines can be advanced from the near-end of transmitter and passed one of catheter lumen, and then arrive the near-end of conduit.In this, line can be soldered to electric connector.

Can add conduit in many ways to like the disclosed sensor module of this paper.For example, perforate can be provided in catheter body and can transmitter or sensor module be installed in open interior place, chamber, so that transmitter can directly contact with blood.On the one hand, all infusion orifices of transmitter or sensor module close conduit are placed.In this structure, transmitter will be prevented from or minimize measurement, otherwise measurement is the haemoconcentration of detectable infusate concentration rather than analyte.On the other hand, method of attachment can be the breach on the catheter body outside and transmitter is fixed in this breach.This can have the partially isolated added benefit of temperature effect with transmitter and any interpolation infusate.The perforate that each end of dimple can have cutting is with 1) far-end and 2 of set sensor) allow the chamber to carry pickup wire to arrive junctor at the catheter proximal end place.

Preferably, the position of sensor module in conduit will be near any infusion orifice (trip) above that, to stop or to minimize the influence of IV solution to analysis measurement.On the one hand, sensor module can be near the about 2.0mm of any infusion orifice of conduit or nearer.

On the other hand, sensor module can be configured so that can adopt flushing line (being salt brine solution), but to allow sensor module to clean out any material of its function of interfere.

The sterilization of transmitter or sensor module

Usually, the suitable equipment of transmitter or sensor module and transmitter was being sterilized before for example in object, using.Can use radiation (for example, electron beam irradiation or gamma radiation), oxyethane or instantaneous-UV sterilization or other known means of this area to realize sterilization.

If any, transmitter, sensor module or be fit to receives and the single use portion of holding the equipment of transmitter is preferably for example used electron beam irradiation or gamma radiation or other known method sterilizations.In the equipment of assembling or any disposable unit can be packaged in sealing fully the gas impermeable container or sack.

Referring now to figure,, Fig. 1 is the amperometric sensor 11 of flex circuits form, and this flex circuits has been incorporated the disclosed transmitter embodiment of this paper into.Transmitter or transmitter 11 can be in substrates 13 (for example, the deflection substrate, such as with the Copper Foil of polyimide lamination) form.One or more electrodes 15,17 can be connected or be bonded to substrate 13 surfaces with 19.Transmitter 11 shows to have reference electrode 15, counter electrode 17 and working electrode 19.In another embodiment, one or more other working electrodes can be included in the substrate 13.But electric wire 210 transmission powers are used to keep oxidation or reduction reaction and go back the testing circuit (not shown) of portability signalling current to the measured parameter of indication to electrode.Measured parameter can be in the hematochemistry thing, exist or maybe be from any analytes of interest analytes of hematochemistry thing.In one embodiment, interested analyte can be a hydrogen peroxide, and its reaction by glucose and P-FAD forms, and therefore has and the proportional concentration of blood sugar concentration.

Fig. 2 describes the sectional view of the disclosed operative sensor of this paper aspect.When transmitter is exposed to some reactant, during the reactant for example in blood flow, found, be selected the enzyme layer 210 that carries out chemical reaction and optional electrode layer 215 away from the electroactive surface of working electrode by part coating at least.For example, in the embodiment of glucose sensor, enzyme layer 210 can comprise P-FAD, such as can be from black mold (Aspergillus niger) (EC 1.1.3.4), II type or VII type.Enzyme layer 210 can be the even or heterogeneous mixture of layer with electrode layer 215, and is indicated such as combination layer 225.Comprise that further from the electroactive surface coating the unitary obscurant of vinyl ester monomers reduces layer 230 than enzyme layer 210.Comprise that the unitary obscurant minimizing of vinyl ester monomers layer 230 at least partly covers the enzyme layer and works to stop also that obscurant and minimizing hydrogen peroxide spread from the enzyme layer.Limiting membrane 205 covers enzyme layers 210 and comprises that the unitary obscurant of vinyl ester monomers reduces layer 230 and part electroactive surface at least.Limiting membrane 205 optionally allows to diffuse to enzyme layer 210 with the blood constitutent of enzyme reaction from blood.In the glucose sensor embodiment, a large amount of oxygen of limiting membrane 205 processes, and optionally limit glucose to enzyme layer 210.In addition, the limiting membrane 205 with adhesive properties can mechanically be sealed to lower floor and/or working electrode with enzyme layer 210, and also can working electrode be sealed to sensor base.Limiting membrane by the EVA polymer formation can play flow restrictor at the top end of electrode, but also plays the effect of sealing agent or encapsulants at enzyme/boundary electrode place and electrode/substrate boundary place.The antithrombotic that comprises biocompatibility forms material and can be added on the limiting membrane 205 such as the live other biocompatible layer (not shown) of heparin derivatives of heparin.

Fig. 3 shows the sectional view on the other hand of the disclosed transmitter of this paper.Therefore, comprise that the unitary obscurant of vinyl ester monomers reduces layer 235 away from the electroactive surface coating and work to stop obscurant.Aspect this, comprise that the unitary obscurant of vinyl ester monomers reduces layer 235 and allows to arrive electroactive surface from the hydrogen peroxide process of enzyme layer.Enzyme layer 210 is than comprising that vinyl ester monomers unitary 235 arranges further from electroactive surface.Like what shown, independent electrode layer 215 at least partly covers the electroactive surface of working electrode.Limiting membrane 205 covers enzyme layers 210 and obscurant and reduces layer 235 and partial electrode at least.

Fig. 4 shows the sectional view on the other hand of the disclosed transmitter of this paper.Aspect this, the enzyme layer is clipped between first polymer layer and the second polymer layer, and at least one of first polymer layer and the second polymer layer comprises the vinyl ester monomers unit.The first polymer layer 235a stops that obscurant arrives electroactive surface, and the second polymer layer 230a reduces hydrogen peroxide and spreads from the enzyme layer.Therefore, the first polymer layer 235a is away from electroactive surface coating and work to stop obscurant.Aspect this, the first polymer layer 235a allows to arrive electroactive surface from the hydrogen peroxide process of enzyme layer.Enzyme layer 210 is arranged further from electroactive surface than obscurant layer 235.Like what shown, independent electrode layer 215 at least partly covers the electroactive surface of working electrode.The second polymer layer 230a arranges further from electroactive surface than enzyme layer 210.The second polymer layer 230a at least partly covers the enzyme layer and works to stop obscurant and reduce hydrogen peroxide and spreads from the enzyme layer.Limiting membrane 205 covers enzyme layers 210 and the first polymer layer 230a and the second polymer layer 235a and partial electrode at least.

Existing referring to Fig. 5-6, property embodiment has as an example been discussed the transmitter aspect of the medullary ray conduit that is fit to have transmitter or sensor module, and it is not limited to any concrete intravenously equipment.Fig. 5 is presented at the sensor module in the multi-cavity catheter.Conduit tube component 10 can comprise a plurality of infusion orifice 11a, 11b, 11c, 11d and at its one or more electric connectors 130 at most proximal end place.Chamber 15a, 15b, 15c or 15d can connect each infusion orifice 11a, 11b, 11c or 11d respectively to meet 190.Similarly, conduit 170 can connect electric connector 130 to meet 190, and can end at meet 190, or ends at one of chamber 15a-15d (as shown in).Although the embodiment that in Fig. 5, shows is the multi-cavity catheter with 4 chambeies and 1 electric connector, other embodiments with other combinations of chamber and junctor are possible, comprise single lumen catheter, have the conduit of a plurality of electric connectors etc.In another embodiment, chamber and electric connector can be probe or other transmitter erecting equipments keep, or chamber can it the proximal end opening and be designed for and insert probe or transmitter erecting equipment.

The far-end of conduit tube component 10 is shown in more detail among Fig. 6.In the one or more midway along far-end, pipe 21 can limit the mouth that one or more outer walls that pass it form.These can comprise middle port 25a, 25b and 25c and the end port 25d that can form at the distal tip place of pipe 21.Each mouthful 25a-25d can distinguish one of corresponding cavity 15a-15d.That is, each chamber can limit the autonomous channel that extends to one of mouth of pipe 25a-25d from one of infusion orifice 11a-11d.Can sensor module be provided to sensitive context through being placed on one or more mouthfuls of places, to provide and the contacting of medium to be analyzed.

The medullary ray conduit can be known in this area and typically be used in CICU (the ICU)/first-aid room of hospital, arrives patient's (different drug is sent in different chambeies) with the one or more chambeies delivering drugs through conduit.A medullary ray conduit typically end and infusion apparatus (for example, infusion pump, IV liquid-drop machine or syringe port) connects and the other end inserts near the aorta of patient's heart or vein with delivering drugs.According to needs of patients, the infusion apparatus delivering drugs, such as, but be not limited to salt solution, medicine, VITAMINs, medicine, protein, peptide, Regular Insulin, neurotransmitter or analogue.In optional embodiment, the medullary ray conduit can be used in any body space or the blood vessel, such as intraperitoneal zone, lymph gland, subcutaneous space, lung, digestive tube or analogue, and can measure except that analyte or curative effect in the blood ectosome liquid.The medullary ray conduit can be a double channel catheter.On the one hand, analyte sensor is building up in the chamber of medullary ray conduit and is used for measuring the characteristic level of user's blood and/or body fluid.But, will recognize that further embodiment can be used for measuring the level of other reagent, characteristic or ratio of components such as hormone, SUV, medicine, enriched material, viral load (for example HIV) or analogue.Therefore; Although maybe be mainly describe being used to treat under the glucose sensor situation of mellitus/diabetic syndrome in the disclosed aspect of this paper; But disclosed aspect can be applied to the patient treatment program of in ICU, monitoring physiological characteristic of wide region, includes but not limited to blood gas, pH, temperature and other interested analytes in vascular system.

The method of analyte in the object medium sized vein is provided on the other hand.This method comprises the vascular system that the conduit that sensor module described herein is provided and conduit is introduced object.This method also comprises analyte.

Embodiment

Preparation transmitter-test panel UNF:---aqueous solution of sodium salt, 25wt% (Aldrich)---is diluted to 0.25wt.% with 4-styrene sulfonic acid-maleic acid to use deionized water.Use electronic fluid decollator (EFD), this solution is applied to all working electrode and the blank electrode of flex circuits transmitter, described in Patent Application No. 2007/0200254.After the dispersion, test panel is placed in 60 ℃ of baking ovens about 5 minutes with dry this solution.Subsequently, manually use cot ton tip applicator (swab tip applicator) be applied between about 40 ℃ to about 50 ℃ the ethylene-vinyl acetate copolymer 25wt% of 1wt% in the p-Xylol of heating vinyl acetate (Aldrich) and about 60 ℃ dry about 20 minutes down.With the solution of this heating be applied to previous with 4-styrene sulfonic acid-maleic acid---sodium salt, 25wt% solution---at some, but working electrode that is coated with on the transmitter on the not all UNF test panel and blank electrode.

Use the vinyl acetate (Aldrich) (under the room temperature) of the cot ton tip applicator ethylene-vinyl acetate copolymer 40wt% that manually some remaining working electrodes of---sodium salt, 25wt% solution---coating and blank electrode apply 1wt% in the p-Xylol with 4-styrene sulfonic acid-maleic acid to previous.After applying ethylene-vinyl acetate copolymer p-Xylol solution, test panel is placed in 60 ℃ of baking ovens about 20 minutes with drying.

The solution that comprises 5wt% P-FAD, LUTARALDEHYDE and bovine serum albumin then is deposited on all working electrode and the blank electrode, and at room temperature dry about 2 hours.

The whole measuring test plate (panel) is dip coated in the 9wt% of p-Xylol ethylene-vinyl acetate copolymer 40wt% vinyl acetate (Aldrich) at room temperature.The dip coated condition be 2 minutes the residence time and 500mm/ minute withdraw from speed.After the dip coated, the whole measuring test plate (panel) is placed in 60 ℃ of baking ovens about 15 minutes with drying.

Test panel V0051:---aqueous solution of sodium salt, 25wt% (Aldrich)---is diluted to 0.25wt.% with 4-styrene sulfonic acid-maleic acid to use deionized water.Use electronic fluid decollator (EFD), this solution is applied to all working electrode and blank electrode like above-mentioned flex circuits.After the dispersion, test panel is placed in 60 ℃ of baking ovens about 5 minutes with drying.Subsequently, apply the vinyl acetate (Aldrich) of the ethylene-vinyl acetate copolymer 12wt% of 1.5wt% in the p-Xylol that is heated to 60 ℃ through dip coated.The dip coated condition be 2 minutes the residence time and 500mm/ minute withdraw from speed.Subsequently, test panel V0051 is placed in 60 ℃ of baking ovens about 25 minutes with drying.

The solution that comprises 5wt% P-FAD, LUTARALDEHYDE and bovine serum albumin then is deposited on all working electrode and the blank electrode.After applying glucose oxidase solution, test panel is kept at room temperature about 30 minutes with drying.

The middle dip coated of whole measuring test plate (panel) 9wt% ethylene-vinyl acetate copolymer 40wt% vinyl acetate (Aldrich) in being heated to about 30 ℃ p-Xylol.Stain coating condition be 2 minutes the residence time and 500mm/ minute withdraw from speed.After the dip coated, the whole measuring test run is placed in 60 ℃ of baking ovens about 15 minutes with drying.

The glucose susceptibility characterizes

Transmitter respectively order immerse glucose concn be 100,200 and a series of glucose solutions of 400mg/dL in.Transmitter is connected to potentiostat and recording of output signals.Figure as the sensor current of the function of glucose concn is that each transmitter produces glucose susceptibility slope (electric current/mg ^-1DL ^-1).

The sign of acetaminosalol susceptibility: the transmitter like above-mentioned preparation is placed in the acetaminosalol solution of 2mg/dL.Transmitter is connected to potentiostat and writes down sensor current.This acetaminosalol sensor current is through changing into glucose signals of equal value with this electric current divided by above-mentioned glucose slope susceptibility.The data of each transmitter are summarised in the table.

Data in the table clearly illustrate that the unitary layer of the wt.% Vinyl Acetate Monomer that comprises the reduction level stops/reduce known disturbances thing acetaminosalol effectively, indicates like the glucose concn of equal value that calculates.Therefore, based on the data and the extrapolation of table, think about 33wt.% or still less the unitary layer of Vinyl Acetate Monomer be effective as obscurant and reduce layer, and think about 25wt.% or still less the unitary layer of Vinyl Acetate Monomer especially be effective as obscurant minimizing layer.And, comprise about 33wt.% or still less the unitary obscurant of Vinyl Acetate Monomer reduce the functional living being transmitter that layer and the overcoating combinations of the flow restriction layer that combines about 40wt.% or more vinyl acetates provide the interior and external use of suitable body.Particularly, the obscurant that comprises ethylene-vinyl acetate copolymer reduce layer and 25wt.% or still less the top coating of flow restriction layer of ethylene-vinyl acetate copolymer that combines make up about 40wt.% vinyl acetate content of vinyl acetate content the functional living being transmitter of the interior and external use of especially suitable body is provided.

Therefore all reference papers that this paper quotes include but not limited to disclosed and undocumented application, patent and reference, by reference with their whole this paper of incorporating into and become the part of this specification sheets.Under the publication of incorporating into by reference and patent or patented claim and the conflicting situation of disclosure that in specification sheets, comprises, this specification sheets is intended to replace and/or has precedence over any such contradiction material.

All numerals that are expressed as component, reaction conditions etc. of using in this manual can be regarded as is in all cases modified by term " approximately ".Therefore, only if point out that on the contrary, the digital parameters that this paper proposes can be an approximation, it can change according to the desirable properties of seeking to obtain.Show no sign of and do not attempt the application of doctrine of equivalents of any claim scope of any application of requirement for restriction the application right of priority, each digital parameters should be explained according to number of significant figures and conventional choice method.

Describe above and disclose several method and material.These are described in method and the material aspect is improved easily, and are changing easily aspect making method and the device.According to the consideration to the disclosure or disclosure enforcement, these modifications are conspicuous to those skilled in the art.Therefore, the disclosure is not intended to be limited in the disclosed embodiment of this paper, but the institute that it covers within claim true scope and the spirit changes and substitutes.

Claims (24)

1. electrochemical analyte sensor, it comprises:

At least one electrode with electroactive surface;

Unitary at least one obscurant of arranging away from said electroactive surface of vinyl ester monomers that comprises reduces layer;

Enzyme layer away from said electroactive surface layout; With

Be arranged in said at least one obscurant and reduce the limiting membrane on layer and the said enzyme layer.

2. transmitter according to claim 1, wherein said at least one obscurant reduce layer and arrange further from said electroactive surface than said enzyme layer.

3. transmitter according to claim 1, wherein said enzyme layer reduce layer than said at least one obscurant and arrange further from said electroactive surface.

4. transmitter according to claim 1, wherein said enzyme layer reduces between the layer at least two obscurants, and at least one obscurant layer comprises the vinyl ester monomers unit.

5. according to each described transmitter of claim 1-4, it is ethylene-vinyl acetate copolymer that wherein said at least one obscurant reduces layer.

6. transmitter according to claim 5, wherein said at least one obscurant reduce layer and comprise 33wt.% or the vinyl acetate content of wt.% still less.

7. according to each described transmitter of claim 1-4, wherein said at least one obscurant reduces layer and comprises:

The mixture of ethylene-vinyl acetate copolymer has the vinyl acetate content of about 12wt.% and about 18wt.% independently;

The mixture of ethylene-vinyl acetate copolymer has the vinyl acetate content of about 12wt.% and about 25wt.% independently;

The mixture of ethylene-vinyl acetate copolymer has the vinyl acetate content of about 18wt.% and about 25wt.% independently;

The mixture of ethylene-vinyl acetate copolymer has the vinyl acetate content of about 12wt.% and 33wt.% independently;

The mixture of ethylene-vinyl acetate copolymer has the vinyl acetate content of about 18wt.% and 33wt.% independently;

The mixture of ethylene-vinyl acetate copolymer has the vinyl acetate content of about 25wt.% and 33wt.% independently; Or

The mixture of ethylene-vinyl acetate copolymer has 33wt.% or the vinyl acetate content of wt.% still less independently.

8. according to each described transmitter of claim 1-4, wherein said at least one obscurant reduces layer and comprises having the about 18wt.% or the ethylene-vinyl acetate copolymer of wt.% vinyl acetate content still less.

9. according to each described transmitter of claim 1-4, further comprise reference electrode, counter electrode, supporting electrode or its combination, arrange at least one stain-proofing layer above that.

10. according to each described transmitter of claim 1-4, wherein said enzyme layer comprises hydrophilic polymer-enzyme composition.

11. according to each described transmitter of claim 1-4; Wherein said enzyme layer comprises hydrophilic polymer-glucose oxidase compositions; Wherein said hydrophilic polymer-enzyme composition comprises and is selected from following material: poly-N-vinyl pyrrolidone, poly-N-vinyl-3-ethyl-2-pyrrolidone, poly-N-vinyl-4,5-dimethyl--2 pyrrolidone, polyvinyl imidazol, gather-the N-N-DMAA, SEPIGEL 305 and its multipolymer.

12. transmitter according to claim 11; Wherein said limiting membrane is selected from: the polycarbonate of urethane, vinyl polymer, polyethers, polyester, polymeric amide, track etching, ZGK 5, gather carbon siloxanes, Mierocrystalline cellulose, protein-based material and its mixture or combination.

13. transmitter according to claim 11, wherein said limiting membrane are the ethylene-vinyl acetate copolymers that comprises about 40wt.% vinyl acetate.

14. electrochemical analyte sensor, it comprises:

At least one electrode with electroactive surface;

Away from the ethylene-vinyl acetate copolymer layer that said electroactive surface is arranged, said ethylene-vinyl acetate copolymer has 33wt.% or the vinyl acetate content of wt.% still less;

Away from having 33wt.% or the enzyme layer arranged of the said ethylene-vinyl acetate copolymer of wt.% vinyl acetate content still less, wherein said enzyme layer comprises the mixture of P-FAD and poly-N-vinyl pyrrolidone; With

Have greater than the ethylene-vinyl acetate copolymer layer on the said enzyme layer of being arranged in of 33wt.% vinyl acetate content.

15. the method for analyte in the measuring object, said method comprises:

Electrochemical analyte sensor is provided, and it comprises:

(i) has at least one electrode of electroactive surface;

Unitary at least one obscurant of (ii) arranging away from said electroactive surface of vinyl ester monomers that comprises reduces layer;

The enzyme layer of (iii) arranging away from said electroactive surface; With

(iv) be arranged in said at least one obscurant and reduce the flow restriction layer on layer and the said enzyme layer;

Said electrochemical analyte sensor is contacted with sample from object;

Wherein reduce the amount of the obscurant of the said electroactive surface of arrival that in said sample, exists.

16. method according to claim 15, wherein said unitary at least one obscurant minimizing layer of vinyl ester monomers that comprises is arranged further from said electroactive surface than said enzyme layer.

17. method according to claim 15, wherein said enzyme layer reduce layer than said at least one obscurant and arrange further from said electroactive surface.

18. being arranged in each, method according to claim 15, wherein said enzyme layer comprise that unitary at least two obscurants of vinyl ester monomers reduce between the layer.

19. according to each described method of claim 15-18, it is to have the 33wt.% or the ethylene-vinyl acetate copolymer of wt.% vinyl acetate content still less that wherein said at least one obscurant reduces layer.

20. according to each described method of claim 15-18, it is to have the about 18wt.% or the ethylene-vinyl acetate copolymer of wt.% vinyl acetate content still less that wherein said at least one obscurant reduces layer.

21. according to each described method of claim 15-18, wherein said limiting membrane is the ethylene-vinyl acetate copolymer that comprises about 40wt.% vinyl acetate.

22. according to each described method of claim 15-18, wherein said sample is the body internal jugular vein blood of object.

23. according to each described method of claim 15-18, wherein said electrochemical analyte sensor is arranged in the conduit.

24. according to each described method of claim 15-18, further comprise reference electrode, counter electrode, supporting electrode or its combination, arrange at least one stain-proofing layer above that.

Images